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Prediction is the Key to Prevention
CHORI Scientists Demonstrate First-Time Gene Association for Type 1 Diabetes

April, 2013 – CHORI Scientists Janelle Noble, PhD, Henry Erlich, PhD, and their colleagues have shown for the first time that a human leukocyte antigen (HLA) allele, HLA-DRB1*03:02, independently contributes to type 1 diabetes (T1D) disease risk.

“While the association of HLA-DRB1 alleles with T1D is very well established, no one has previously identified the role of alleles at the secondary HLA-DRB3, 4, and 5 loci,” says Dr. Noble. “What our data shows for the first time is that at the secondary locus, it does in fact seem to matter whether you have the DRB3*01:01 or DRB3*02:02 allele: the DRB3*02:02 allele confers a greater risk for T1D.”

“What our data shows for the first time is that at the secondary locus, the DRB3*02:02 allele confers a greater risk for T1D.”



T1D is genetic disease in which affected individuals lose the ability to produce insulin. T1D, formerly called "juvenile diabetes," was previously recognized only in children, but it is becoming more and more prevalent, with ages of disease onset reaching well into adulthood. Consequently, researchers have been searching for decades to identify all of the genetic contributions to T1D.

An international collaboration providing the largest sample sizes to date, the Type 1 Diabetes Genetics Consortium (T1DGC), has provided researchers with unparalleled opportunities to dig deeper into the genetic causes of T1D. As a result of this large study, Drs. Noble, Erlich and their colleagues were able to assess for the first time the contribution to disease risk of three alleles, DRB3, DRB4 and DRB5.

“We've looked at the DRB1 gene for a long time, but DRB1 is not the only gene that encodes the beta chain of the DR molecule. Everyone has a DRB1 gene on each chromosome 6, but other DRB genes are present as well, depending on what is at the DRB1 gene.”
Researchers haven't investigated whether or not these secondary loci, which include DRB3, 4 and 5, influence disease risk for a couple of reasons. One reason is that DRB3, DRB4, and DRB5 are not very polymorphic which means they don't change very much from person to person-compared to DRB1. The other reason no one has looked further into the affect of DRB 3, 4, or 5 is that with traditional genotyping methodology, these alleles used to cause a confounding affect.

As Dr. Noble explains, "We would be trying to determine whether DRB1 itself was causing disease risk and these other alleles would get in the way. This has meant that historically researchers actually have tried to avoid looking at the contribution to disease risk of DRB3, 4 or 5 so as not to confuse the DRB1 results."

With the advent of next generation sequencing, however, researchers now can look at multiple loci at the same time in the same sequencing experiment without any ambiguity about which allele came from which chromosome.

As a result, Drs. Noble, Erlich and their colleagues were able to identify that the DRB3*02:02allele is, in fact, associated with greater risk for T1D.

While affordable, population-wide genetic screening for T1D is far in the future, the only way such screening will be effective is if all of the genes that confer T1D risk are fully understood. Drs. Noble and Erlich's latest publication provides one more piece of the puzzle to predicting, and ultimately, preventing T1D.

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Monday, May 20, 2013 3:21 PM

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